Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials

Saranya Chumsri, Zhuo Li, Daniel J. Serie, Nadine Norton, Afshin Mashadi-Hossein, Kathleen Tenner, Heather Ann Brauer, Sarah Warren, Patrick Danaher, Gerardo Colon-Otero, Ann H. Partridge, Lisa A. Carey, Florentine Hilbers, Veerle Van Dooren, Eileen Holmes, Serena Di Cosimo, Olena Werner, Jens Bodo Huober, Amylou C. Dueck, Christos SotiriouCristina Saura, Alvaro Moreno-Aspitia, Keith L. Knutson, Edith A. Perez, E. Aubrey Thompson

Research output: Contribution to journalArticlepeer-review


Trastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49–0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67–1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ2p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09–25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24–36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).

Original languageEnglish (US)
Article number68
Journalnpj Breast Cancer
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)


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